Cyclodepsipeptide compound

ABSTRACT

A compound of the formula: ##STR1## wherein A is benzyl group which has suitable substituent (s), A a , B and D are each lower alkyl, 
     C is hydrogen or lower alkyl, 
     or a salt thereof. 
     The compound or its salt of the present invention has excellent parasiticidal activities as parasiticides (anthelmintics) for animals and human bodies.

TECHNICAL FIELD

The present invention relates to new depsipeptide derivatives havingantiparasitic activity.

BACKGROUND ART

Japanese Kokai Tokkyo Koho 3-35796 and 5-170749 disclose depsipeptidederivatives prepared by culturing microorganisms.

As depsipeptide substances having parasiticidal activity, substancePF1022 (Japanese Kokai Tokkyo Koho 3-35,796) and substance PF1022B,substance PF1022C, substance PF1022D (Japanese Kokai Tokkyo Koho5-170,749) are known, and among these compounds the effectiveness ofsubstance PF1022 on gastrointestinal parasites (whipworms, haemonchus,hairworms and roundworms living in the stomach and intestine) has beenconfirmed. This time, the object was to find a drug having a strongereffect on gastrointestinal parasites and also effective on tissueparasites (for example filariid worms living in blood vessels, lungwormsliving in the lungs, liver flukes living in the liver).

DISCLOSURE OF INVENTION

The object compound of the present invention, depsipeptide derivatives(I) can be represented by the following general formula: ##STR2##wherein A is benzyl group which has suitable substituent (s), A^(a), Band D are each lower alkyl, and

C is hydrogen or lower alkyl.

According to the present invention, the object compound, thedepsipeptide derivatives (I) can be prepared by the following processes.

It should be indicated that any of D-configured compound, L-configuredcompound and/or DL-configured compound are included in the scope of thepresent invention; however, for the convenience, only D-configuredcompounds and L-configured compounds are explained in the process forpreparation as follows. ##STR3## wherein A, A^(a), B, C and D are eachas defined above, R is hydrogen or amino protective group,

A¹ is benzyl group or benzyl group which has lower alkoxy,

A² is benzyl group which has nitro, or benzyl group which has nitro andlower alkoxy,

A³ is benzyl group which has amino, or benzyl group which has amino andlower alkoxy,

A⁴ is benzyl group which has mono- or di- lower alkylamino, or benzylgroup which has mono- or di- lower alkylamino and lower alkoxy,

A⁵ is benzyl group which has cyclic amino, or benzyl group which hascyclic amino and lower alkoxy,

A⁶ is benzyl group which has hydroxy, or benzyl group which has hydroxyand lower alkoxy,

A⁷ is benzyl group which has lower alkoxy,

A⁸ is benzyl group which has protected amino and

A⁹ is benzyl group which has amino.

Throughout the present specification, the amino acids, peptides,protective groups, condensing agents, etc. are indicated by theabbreviations according to the IUPAC-IUB (Commission on BiologicalNomenclature) which are in common use in the field of art.

Moreover, unless otherwise indicated, the amino acids and their residueswhen shown by such abbreviations are meant to be L-configured compoundsand residues, and when shown by D-abbreviations, they are meant to beD-configured compounds and residues.

In the present invention, there are employed the followingabbreviations.

p-Me₂ NPhLac:3-(4-dimethylaminophenyl)-2-hydroxypropionic acid[β-(p-dimethylaminophenyl)lactic acid]

p-MorPhLac:2-hydroxy-3-(4-morpholinophenyl)propionic acid[β-(p-morpholinophenyl)lactic acid]

p-MeOPhLac:2-hydroxy-3-(4-methoxyphenyl)propionic acid[β-(p-methoxyphenyl)lactic acid]

Lac:2-hydroxypropionic acid [lactic acid]

p-NO₂ PhLac:2-hydroxy-3-(4-nitrophenyl)-propionic acid[β-(p-nitrophenyl)lactic acid]

p-NH₂ PhLac:3-(4-aminophenyl)-2-hydroxypropionic acid[β-(p-aminophenyl)lactic acid]

p-CbmNHPhLac:2-hydroxy-3-(4-methoxycarbonylaminophenyl)propionic acid[β-(p-methoxycarbonylaminophenyl)lactic acid]

Suitable salts of the compound (I) are conventional non- toxic salt andmay include a salt with a base or an acid addition salt such as a saltwith an inorganic base, for example, an alkaline metal salt [e.g. sodiumsalt, potassium salt, cesium salt, etc.], an alkaline earth metal salt[e.g. calcium salt, magnesium salt, etc.], an ammonium salt; a salt withan organic base, for example, an organic amine salt [e.g. triethylaminesalt, pyridinium salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.];an inorganic acid addition salt [e.g. hydrochloride, hydrobromide,sulfate, phosphate,etc.]; an organic carboxylic or sulfonic acidaddition salt [e.g. formate, acetate, trifluoroacetate, maleate,tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.];a salt with a basic or acidic amino acid [e.g. arginine salt, asparticacid salt, glutamic acid salt, etc.]; and the like.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions to beincluded within the scope of the invention are explained in detail asfollows.

The term "lower" is intended to mean 1 to 6 carbon atom (s), preferably1 to 4 carbon atom (s), unless otherwise indicated.

Suitable substituent (s) in the term "benzyl group which has substituent(s)" may include hydroxy, lower alkoxy, lower-alkoxy-lower-alkoxy,lower-alkoxy-lower-alkoxy-lower-alkoxy, lower alkyl, amino, protectedamino, mono- or di- substituted lower alkyl amino, cyclic amino, nitro,halogen [e.g. fluoro, chloro, bromo, iodo, etc.], and the like. Thesemay have one or more than one substituents.

Suitable "lower alkyl" may include a straight or branched one having 1to 6 carbon atom (s) such as methyl, ethyl, n-propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, hexyl.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, andthe like.

Suitable "lower-alkoxy-lower-alkoxy" may include methoxymethoxy,methoxyethoxy, methoxypropoxy, ethoxyisopropoxy, and the like.

Suitable "lower-alkoxy-lower-alkoxy-lower-alkoxy" may includemethoxymethoxyethoxy, methoxyethoxyethoxy, methoxyethoxypropoxy,ethoxymethoxyisopropoxy, and the like.

Suitable "cyclic amino" may be an aromatic ring or an alicycliccompoundwhich has one or more than one nitrogen atom (s) as hetero atom (s) andmay be monocyclic or condensed polycyclic group which may be saturatedor unsaturated. Cyclic amino group may further contain hetero atom (s)such as one or more than one nitrogen atom (s), oxygen atom (s), sulfuratom (s), and the like.

Still further the cyclicamino group may be a spiro ring or a bridgedcyclic compound. The number of the constructive atoms of the cyclicamino group is not limited but, for example, monocyclic group has a 3 to8-membered ring and bicyclic group has 7 to 11-membered rings.

Example of such cyclic amino may include saturated or unsaturatedmonocyclic group containing one nitrogen atom as hetero atom such as1-azetidinyl, pyrrolidino, 2-pyrroline-1-yl, 1-pyrrolyl, piperidino,1,4-dihydropyridine-1-yl, 1,2,5,6-tetrahydropyridine-1-yl,homopiperidino; saturated or unsaturated monocyclic group containingmore than one nitrogen atoms as hetero atoms such as 1-imidazolidinyl,1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 1-tetrazolyl, 1-piperazinyl,1-homopiperazinyl, 1,2-dihydropyridazine-1-yl,1,2-dihydropyrimidine-1-yl, perhydropyrimidine-1-yl,1,4-diazacycloheptane-1-yl; saturated or unsaturated monocyclic groupcontaining 1 to 2 oxygen atom (s) and 1 to 3 nitrogen atom (s) as heretoatoms such as oxazolidine-3-yl, 2,3-dihydroisoxazole-2-yl, morpholino;saturated or unsaturated monocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom (s) as hetero atoms such asthiazolidine-3-yl, isothiazoline-2-yl, thiomorpholino; condensedpolycyclic group such as indole-1-yl, 1,2-dihydrobenzimidazole-1-yl,perhydropyrrolo[1,2-a]pyrazine-2-yl; spirocyclic group such as2-azaspiro[4,5]decane-2-yl; bridged heterocyclic group such as7-azabicyclo[2,2,1]heptane-7-yl; and the like.

Suitable "mono- or di-lower alkylamino" may include amino groupsubstituted by one or two lower alkyl (s) [e.g. methyl, ethyl,isopropyl, t-butyl, t-pentyl, etc.], preferably methylamino, ethylamino,dimethylamino, diethylamino, di-n-propylamino, diisopropylamino,dibutylamino, etc.

"Amino protective group" and "Amino protective group" in the term"protected amino" may include acyl such as lower alkanoyl [e.g. formyl,acetyl, propionyl, pivaloyl, hexanoyl, etc.], mono (or di or tri) halo(lower) alkanoyl [e.g. chloroacetyl, bromoacetyl, dichloroacetyl,trifluoroacetyl, etc.], lower alkoxycarbonyl [e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl,hexyloxycarbonyl, etc.], carbamoyl, aroyl [e.g. benzoyl, toluoyl,naphthoyl, etc.], ar (lower) alkanoyl [e.g. phenylacetyl,phenylpropionyl, etc.], aryloxycarbonyl [e.g. phenoxycarbonyl,naphthyloxycarbonyl,etc.], aryloxy (lower) alkanoyl [e.g. phenoxyacetyl,phenoxypropionyl, etc.], arylglyoxyloyl [e.g. phenylglyoxyloyl,naphthylglyoxyloyl, etc.], ar (lower) alkoxycarbonyl which may havesuitable substituent (s) [e.g. benzyloxycarbonyl, phenethyloxycarbonyl,p-nitrobenzyloxycarbonyl, etc.]; ar (lower)alkyl such as ar(lower)alkylidene which may have substituent (s) [e.g. benzylidene,hydroxybenzylidene, etc.], mono (or di or tri) phenyl (lower) alkyl[e.g. benzyl, phenethyl, benzhydryl, trityl, etc.]; and the like.

Above-mentioned amino protective group contains the protective groupwhich has the function to temporarily protect amino group and is oftenused in the field of amino acid and peptide chemistry.

Suitable "benzyl group which has lower alkoxy" may include loweralkoxy-substituted-benzyl such as 4-methoxybenzyl, 2,4-dimethoxybenzyl,3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2,3,4-trimethoxybenzyl,2-ethoxybenzyl, 4-hexyloxybenzyl, etc.

Suitable "benzyl group which has halogen" may include halogensubstituted-benzyl such as 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl,3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 2-bromobenzyl,2-bromo-4-chlorobenzyl, etc.

Suitable "benzyl group which has lower alkyl" may include loweralkyl-substituted-benzyl such as 4-methylbenzyl, 4-ethylbenzyl,4-propylbenzyl, 4-isopropylbenzyl, 4-butylbenzyl, 4-isobutylbenzyl,4-t-butylbenzyl, 4-pentylbenzyl, 4-hexylbenzyl, 2,3-dimethylbenzyl,2,6-dimethylbenzyl, 3,4-dimethylbenzyl, 2,4,6-trimethylbenzyl,etc.

Suitable example of benzyl group which has such substituent (s) mayinclude lower alkoxy-substituted benzyl [e.g. 4-methoxybenzyl,3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2,3,4-trimethoxybenzyl,2-ethoxybenzyl, 4-hexyloxybenzyl, etc.], halogen substituted benzyl[e.g. 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl,3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 2-bromobenzyl,2-bromo-4-chlorobenzyl, etc.], hydroxy-substituted-benzyl [e.g.2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, etc.], and the like.

More preferable example of "cyclic amino group which may havesubstituent (s)" may include 4-methylpiperazino, and the like.

The processes for preparing the object compound (I) are explained indetail in the following.

Process 1

The object compound (I) or salts thereof can be prepared by subjectingthe compound (II) or its reactive derivative at the amino group orcarboxy group or a salt thereof to cyclization reaction.

The starting compound (II), its reactive derivative or a salt thereofare new and can be prepared by the methods of Preparations mentionedbelow or a similar manner thereto.

Suitable reactive derivative at the amino group of the compound (II) mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound (II) with a carbonyl compoundsuch as aldehyde and ketone; a silyl derivative formed by the reactionof the compound (II) with a silyl compound such as bis (trimethylsilyl)acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea; aderivative formed by the reaction of the compound (II) with phosphorustrichloride or phosgene, and the like.

Suitable reactive derivative at the carboxy group of the compound (II)may include an acid halide,an acid anhydride, an activated amide, anactivated ester, and the like. Suitable example of the reactivederivative may be an add chloride; an acid azide; a mixed acid anhydridewith an acid such as aliphatic carboxylic add [e.g. acetic acid,propionic acid, butyric acid, trichloroacetic acid, etc.] or aromaticcarboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride,and the like. These reactive derivatives can optionally be selected fromthem according to the kind of the compound (II) to be used.

The reaction is carried out in the usual method which is used incyclization reaction, for example, under heating or in the presence of aconventional condensing agent. When R in the compound (II) is aminoprotective group, the elimination of the amino protective group iscarried out prior to ring cyclization reaction.

Suitable condensing agent may include carbodiimide or a salt thereof[e.g. N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-morpholinoethylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl) carbodiimide,N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide or hydrochloridethereof], diphenyl phosphorylazide, diethyl phosphorocyanidate, bis(2-oxo-3-oxazolidinyl) phosphinic chloride, etc.;N,N'-carbonyldiimidazole, N,N'-carbonylbis-(2-methylimidazole);keteneimine compounds [e.g. pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, etc.]; ethoxyacetylene;1-alkoxy-1-chloroethylene; ethyl polyphosphate; isopropyl polyphosphate;phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride;thionyl, chloride; oxalyl chloride; combination of triphenylphosphineand carbon tetrachloride or diazene carboxylate;2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H -benzotriazole;1-hydroxybenzotriazole; so-called Vilsmeierreagent prepared b), thereaction of N,N-dimethylformamide with thionyl chloride, phosgene,phosphorus oxychloride,etc.; or the like.

The reaction in the presence of a condensing agent is usually carriedout in a conventional organic solvent which does not adversely influencethe reaction such as methylene chloride, methanol, ethanol, propanol,acetonitrile, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone,tetrahydrofuran, benzene, toluene, xylene, etc. or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating. Further, cyclization reactionunder heating can be carried out in the above-mentioned organic solventunder heating below boiling point of the solvent.

Process 2

The object compound (Ia) or salts thereof can be prepared by subjectingthe compound (III) or a salt thereof to nitration reaction.

The starting compounds (III) contain known compounds (Japanese KokaiTokkyo Koho 5-170749) and novel compounds. The novel compounds can beprepared by the methods of Preparations and Examples mentioned below ora similar manner thereto.

This reaction is carried out by reacting the compound (III) or a saltthereof with a nitration agent [e.g. nitric acid, nitrate, nitric acidester, acetyl nitrate, nitronium tetrafluoroborate, etc.].

The reaction can usually be carried out in a conventional solvent whichdoes not adversely influence the reaction such as methylene chloride.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling or at ambient temperature.

This reaction can be carried out in substantially the same manner asExample 4 mentioned below.

Process 3

The object compound (Ib) or salts thereof can be prepared by subjectingthe compound (Ia) or a salt thereof to reduction reaction.

This reaction can be carried out in a conventional manner for reducingnitro to amino and it may include chemical reduction and catalyticreduction.

Suitable reducing agents to be used in chemical reduction are acombination of a metal [e.g. tin, zinc, iron, etc.] or a metalliccompound [e.g. chromium chloride, chromium acetate, etc.] and an organicor inorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts [e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.], palladium catalysts [e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.], nickel catalysts[e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobaltcatalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts[e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reducedcopper, Raney copper, Ullman copper, etc.], and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, N,N-dimethylformamide or a mixture thereof.Additionally, in case that the above-mentioned acids to be used inchemical reduction are liquid, they can also be used as a solvent.Further, a suitable solvent to be used in catalytic reduction may be theabove-mentioned solvent and other conventional solvent such as diethylether, dioxane, tetrahydrofuran, or a mixture thereof.

The reaction temperature of this reaction is not critical and thereaction is usually carried out under cooling to warming.

Process 4

The object compound (Ic) or salts thereof can be prepared by subjectingcompound (Ib) or a salt thereof, obtained by the Process 3 with orwithout isolation thereof, to alkylation reaction. This reaction can becarried out by combination of aldehyde and reducing agent, or alkylhalide and base.

Suitable reducing agents may include metal hydride complex compound[e.g. sodium borohydride, sodium cyanoborohydride, potassiumborohydride, bis (2-methoxyethoxy) aluminium hydride, etc.], hydrogen,formic acid or ammonium formate, palladium catalyst [e.g. palladium oncarbon, palladium hydroxide on carbon, palladium black,etc.].

Suitable base may include an inorganic base [e.g. sodium bicarbonate,potassium carbonate, etc.] and an organic base [e.g. pyridine,triethylamine, etc.].

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction.

The reaction by combining aldehyde and reducing agent can be carried outin substantially the same manner as Preparation 2 mentioned below.

The reaction by combining alkyl halide and base can be carried out insubstantially the same manner as Preparation 13 mentioned below.

Process 5

The object compound (Id) or salts thereof can be prepared by subjectingcompound (Ib) or a salt thereof, obtained by the Process 3 with orwithout isolation thereof, to monoalkylation reaction followed byintramolecular alkylation reaction. This reaction can be carried out bycombining a compound having two aldehydes in the molecule and a reducingagent, or by combining a compound having two halogens in the moleculeand a base.

Process 6

The object compound (Ie) or salts thereof can be prepared by subjectingcompound (Ib) or a salt thereof, obtained by the Process 3 with orwithout isolation thereof, to hydroxylation reaction by diazotizationreaction followed by decomposition of diazonium salt. This reaction canbe carried out by reacting the compound (Ib) or a salt thereof withsodium nitrite in the presence of an inorganic or an organic acid anddecomposing a growing diazonium salt in water or an organic acid underthe room temperature to heating, carrying out hydrolysis if necessary.It is possible to prepare the compound (Ie) or salts thereof bytransforming the amino group of the compound (Ib) or a salt thereof intoa hydroxyl group.

Suitable acid may include an inorganic acid [e.g. sulfuric acid,hydrochloric acid, borofluoric acid, etc.] and an organic acid [e.g.acetic acid, trifluoroacetic acid, etc.].

Process 7

The object compound (If) or salts thereof can be prepared by subjectingthe compound (Ie) or a salt thereof, which is obtained by the Process 6,to alkylation reaction. This reaction can be carried out by combining aalkyl halide and a base.

Suitable base may include an inorganic base [e.g. sodium bicarbonate,potassium carbonate, etc.] and an organic base [e.g. pyridine,triethylamine, etc.].

Process 8

The object compound (Ih) or salts thereof can be prepared by subjectingthe compound (Ig) or a salt thereof to removal reaction of the aminoprotective group.

This removal reaction is carried out in a conventional manner such ashydrolysis,reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkaline metal [e.g. sodium, potassium, etc.], an alkaline earthmetal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate orbicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine,etc.], picoline, 1,5-diazabicyclo [4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2] octane, 1,8-diazabicyclo [5.4.0]undec-7-ene, or the like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid,p-toluenesulfonic acid, etc.] and an inorganic acid [e.g. hydrochloricacid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogenbromide, ammonium chloride, etc.]. The removal reaction using Lewis acidsuch as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroaceticacid, etc.] is preferably carried out in the presence of cation trappingagents [e.g. anisole,phenol, etc.].

The reaction is usually carried out in a solvent such as water, alcohol[e.g. methanol, ethanol, etc.], tetrahydrofuran, methylene chloride, amixture thereof or any other solvent which does not adversely influencethe reaction. A liquid base or acid can be also used as a solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

The reduction which can be used for removal reaction includes chemicalreduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of a metal [e.g. tin, zinc, iron, etc.] or a metalliccompound [e.g. chromium chloride, chromium acetate, etc.] and an organicor inorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction may includeplatinum catalysts [e.g. platinum plate, spongy platinum, platinumblack, colloidal platinum, platinum oxide, platinum wire, etc.],palladium catalysts [e.g. spongy palladium, palladium black, palladiumoxide, palladium on carbon, colloidal palladium, palladium on bariumsulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g.reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts[e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reducediron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raneycopper, Ullman copper, etc.] and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, N,N-dimethylformamide or a mixture thereof.Additionally, in case that the above-mentioned acids to be used inchemical reduction are liquid, they can also be used as a solvent.

The reaction temperature of this reaction is not critical and thereaction is usually carried out under cooling to warming.

The compound or its salt of the present invention has excellentparasiticidal activities as parasiticides (anthelmintics) for animalsand human bodies. Particularly it is effective against nematodes,trematodes and cestodes which are infective to the domestic animals,domestic fowls or pets such as pigs, sheep, goats,cattle, horses, dogs,cats and chickens.

Nematodes which can be effectively exterminated by the compound areshown in the following:

Haemonchus genus, Trichostrongylus genus, Ostertagia genus, Nematodirusgenus, Cooperia genus, Ascaris genus, Bunostomum genus, Oesophagostomumgenus, Chabertia genus, Trichuris genus, Strongylus genus, Trichonemagenus, Dictyocaulus genus, Capillaria genus, Heterakis genus, Toxocaragenus, Ascaridia genus, Oxyuris genus, Ancylostoma genus, Uncinariagenus, Toxascaris genus, Parescaris genus, Nippostrongylus genus,Metastrongylus genus, Hyostrongylus genus, Strongyloides genus andCyathostomum genus.

Some kinds of Nematodirus genus, Cooperia genus and Oesophagostomumgenus attack the intestinal canal, just Haemonchus genus and Ostertagiagenus are parasitic on the stomach and parasites of Dictyocaulus genusare found in lungs. The compound is effective against them.

The parasites of Filariidae or Setariidae are found in other tissues andorgans such as heart, blood vessels, hypodermis, lymphatic vessels. Thecompound is also effective against them.

Trematodes which can be effectively exterminated by the compound areshown in the following:

Fasciola genus, Calicophoron genus, Orthocoelium genus and Eurytremagenus.

Cestodes which can be effectively exterminated by the compound are shownin the following:

Anoplocephala genus, Moniezia genus and Dipylidiumc genus.

It is also effective against parasites which infect human beings. Themost common parasites in the alimentary canal of human beings are asfollows:

Ancylostoma genus, Necator genus, Ascaris genus, Strongyloidesgenus,Trichinella genus, Capillaria genus, Trichuris genus and Enterobiusgenus.

It is also effective against other medically important parasites whichis found in the blood or other tissues or organs outside of thealimentary canal, such as Wuchereria genus, Brugia genus, Onchocercagenus and Loa genus in Filariidae, as well as parasites such asDracunlus genus in Dracunculidae. It is also effective against parasitesin the intestinal canal such as Strongyloides genus, Trichinellagenus ina particularly conditioned parasitism outside of the intestinal canal.

Specifically, relationships between different animals and nematodes,trematodes and cestodes parasitic on those animals are as follows:

Parasites parasitic on cattle include stomach worms living in thestomach (Haemonchus, Ostertagia, Trichostrongylus, Cooperia), hookwormsliving in the small intestine (Bunostomum), trichina (Strongyloides),nematodes (Nematodirus), cestodes (Monizia), roundworms living in thelarge intestine (Oesophagostomum, Trituris), liver flukes living in theliver (Fasciola), and lungworms living in the lungs (Dictyocaulus).

Parasites parasitic on sheep include stomach worms living in the stomach(Haemonchus, Ostertagia, Trichostrongylus), parasites living elsewherein the gastrointestinal (Bunostomum, Trichostrongylus, Cooperia,Strongyloides, Oesophagostomum, Taenia, Chabertia, Trituris), lungwormsliving in the lungs (Dictyocaulus, Muellerius, Protostrongylus), andliver flukes living in the liver (Fasciola, Dicrocoelium).

Parasites parasitic on pigs include stomach worms living in the stomach(Hyostrongyloides), roundworms living in the small intestine (Ascaris),trichina (Strongyloides), hog intestine tubercle worms living in thececum (Oesophagostomum), whipworms (Trituris), lungworms living in thelungs (Metastrongylus), and liver flukes living in the liver (Fasciola).

Parasites parasitic on horses include stomach worms living in thestomach (Habronema, Draschia), roundworms living in the small intestine(Parascaris), trichina (Strongyloides), cestodes (Anoplocephala),pinworms living in the large intestine (Oxyuris), liver flukes living inthe liver (Fasciola), and lungworms living in the lungs (Dictyocaulus).

Parasites parasitic on dogs include roundworms living in the smallintestine (Toxocara, Toxascaris), hookworms (Ancylostoma, Uncinaria),trichina (Strongyloides), cestodes (Dipylidium, Taenia), lungwormsliving in the lungs (Capillaria), and filariid worms living in the heart(Dirofilaria).

The compound of this invention also kills plant nematodes and soilnematodes, and therefore can be used as a pest controller inagriculture, grape growing, fruit growing, landscape gardening andafforestation.

In order to illustrate the usefulness of the object compound (I),thepharmacological test data of the representative compounds of thecompound (I) are shown in the following.

Test

Test 1

(1) Test Compound The compound of Example 1.

(2) Test Method

The effect of parasiticides (anthelmintics) was examined with the ratswhich was infected by nematodes which are parasitic on rats,Nippostrongylus brasilienses.

Wistar strain rats (female, 6 weeks old, 120-130 g weight) weresacrificed by infecting them and giving them subcutaneous injections of3000 infective larvae per rat.

Test compound of 50 mg was dissolved in 0.25 ml dimethylsulfoxide, 0.5%methylcellulose aqueous solution was added, and liquid volume wasadjusted to be prescribed volume of 100, 20, 10, 5, 2.5, 1.25, 1.0,0.63, 0.32 mg/kg to utilize. After they were infected, on each 7th, 8thand 9th day, the test compound was administered orally with aboveconcentrations. On the 11th day, the rats were dissected and the numberof parasites in the small intestine were measured.

The given measurement was based to calculate the reduction rate from thepercentage of the number of the parasites of unadministered rats(control).

The result is shown in the Table 1.

(3) Test Result

    ______________________________________                                                           Minimum Amount of                                                             Administration                                                                indicated by more than 85%                                 Test Compounds     of Reduction Rate                                          ______________________________________                                        PF1022             10 mg/kg                                                   (Japanese Kokai Tokkyo Koho 3 -                                               35,796)                                                                       PF1022 - D         20 mg/kg                                                   (Japanese Kokai Tokkyo Koho 5                                                 170,749)                                                                      Example 1           5 mg/kg                                                   ______________________________________                                    

Test 2

(1) Test Compound

The compounds of Example 1 and Example 3.

(2) Test Method

Effectivity against microfilaria was examined with the dogs which wasconfirmed to be infected by heart worm (Dirofilaria immitis).

The capsulated test compounds were orally administered once bycompulsion to the infected dogs with the dosage of 100 mg/kg.

Blood was gathered in 18 hours before administration,in 1 hour and onthe 1st, 2nd and 7th day after the administration and numbers ofmicrofilaria in the blood were inspected by acetone concentrationtechnique of microfilaria.

The result is shown in the Table 2.

(3) Test Result

                  TABLE 2                                                         ______________________________________                                                 Number of microfilaria in 1 ml blood                                          Before                                                               Dose       administra-                                                        Test    (mg/   tion      After administration                                 Compounds                                                                             kg)    18 hrs.   1 hrs.                                                                              1 day 2 day 7 day                              ______________________________________                                        PF1022 - D                                                                            100    152,967   129,900                                                                             76,033                                                                              146,667                                                                             193,350                            Example 1                                                                             100    109,217    56,583                                                                                17    33    180                             Example 3                                                                             100     12,300    8,133                                                                               6,917                                                                               8,000                                                                                 17                              ______________________________________                                    

Test 3

(1) Test Compound

The compounds which are illustrated in Example 1, Example 2 and Example3.

(2) Test Method

The growth inhibiting effect on a free-living nematode (Rhabditiselongtus) was studied.

The test compounds were dissolved in methanol and test compoundsolutions of 2000, 1000, 500, 250, 125 and 62.5 μg/ml were prepared. 1ml of each of these solutions was dripped onto pre-prepared agar in apetri dish (1.5% agar, 10 ml per petri dish) and well dried. 0.5 ml of asuspension of free-living nematodes (about 100 nematodes/ml) was drippedonto each petri dish, and water of the suspension was evaporated byblow-drying. Yeast powder, which is a nutrient source for nematodes, wassprinkled on the agar, and then the petri dishes were covered inparafilm and left to stand at 25° C. for 24 hours. The effect was judgedby observing the worms under a microscope and measuring the minimumconcentration of test compound with which eliminated motility,

The result is shown in the Table 3.

(3) Test Result

                  TABLE 3                                                         ______________________________________                                                       Minimum effective                                                             concentration                                                  Test Compounds (μg/ml)                                                     ______________________________________                                        PF1022 - D     >2000                                                          Example 1       500                                                           Example 2      1000                                                           Example 3      1000                                                           ______________________________________                                    

When the compounds of the present invention are used for animals andhuman being as parasiticides (anthelmintics), it can be administeredorally as a liquid drink. The liquid drink is usually solution,suspension or dispersed solution in a suitable non-toxic solvent orwater in admixture with suspending agent such as bentonite, wettingagent or excipient, and it generally contains liquid drink orantifoaming agent. The prescription of a liquid drink generally contains0.01˜0.5 weight%, preferably 0.01˜0.1 weight% activated compound. Whenit is preferably administered orally as a dried solid single dose,capsules, pills, or tablets, which contains the desired amount ofactivated compound are usually used. These forms of dosage are preparedby homogeneous admixtures of diluent, filler, disintegrator and/orexcipient such as dextrine, lactose, talc, magnesium stearate, vegetablerubber. The usage of such single dose prescription can be varied broadlyreferring to the weight and containing quantity of parasiticides(anthelmintics) depending upon kind of hosts, kind of parasites andweight of hosts which are to be treated.

When it is administered in animal feed, it is used as to dispersehomogeneously, or as top dressing, or in the form of pellet. To achievepreferable antiparasitic effect, the activated compound of 0.0001˜2% isusually contained in feed.

The dosage which was dissolved or dispersed in liquid carrier excipientscan be administered to animals parenterally by giving them injections inthe anterior stomach, muscle, trachea, or under the skin. The activatedcompound is mixed with suitable vegetable oil such as peanut oil,cottonseed oil for parenteral administration. These prescriptionsgenerally contain the activated compound of 0.05˜50 weight%.

It can also be administered locally by mixing in a suitable carrier suchas dimethylsulfoxide or hydrocarbon solvent. The prepared pharmaceuticalcan be used directly on the exterior of animals by spraying or directinjections.

Among the compounds of the invention, compounds which are hardly solublein water are improved in its absorption characteristics into alimentarycanal by various well-known pharmaceutical techniques for improvingsolubility. The pharmaceutical techniques concerning the matter mayinclude the method for preparing a pharmaceutical composition containingat least one kind of surfactants and/or fats and oils (Japanese KokaiTokko Koho 4-221312, 5-70366), the method for dispersing a medicine ofsolid state into an inactive carrier in monomolecular state (JapaneseKokai Tokko Koho 5-262642), and the like.

Concretely the surfactant may include fatty acid esters of glycerine,fatty acid esters of sorbitan, fatty acid esters of polyoxyethylenesorbitan, fatty acid esters of polyoxyethylene glycerine,polyoxyethylene hydrogenated castor oils, fatty acid esters of sucrose,polyoxyethylene polyoxypropylene glycol, polysorbate, and the like. Thefat and oil may include soybean oil, tallow, hydrogenated oils, almondoil, olive oil, sesame oil, and the like. The inactive carrier mayinclude low viscosity hydroxypropyl cellulose, and the like.

The most suitable usage amount of the activated compound to achieve themost effective result depends on the kind of animals which are to betreated, and type of parasitic infection and its stage.

It can be achieved by oral administration of the activated compound0.01˜100 mg, preferably 0.5˜50.0 mg per kg of the treated animal.

Such dosage amount is given in a relatively short term of 1˜5days atonce or separately.

The following Preparations and Examples are given for the purpose ofillustrating the present invention.

Preparation 1

To a solution of ethyl (R)-2-acetoxy-3-(4-nitrophenyl) propionate (5.62g) in ethanol (50 ml) was added conc. hydrochloric acid (2.5 ml) and 10%palladium on carbon (0.6 g) and the mixture was hydrogenated underatmospheric pressure of hydrogen gas for 3 hours at ambient temperature.The catalyst was filtered off and the filtrate was evaporated in vacuo.To the obtained residue was added 0.05N Hydrochloric acid (200 ml) andwashed with ether (100 ml×2). Saturated sodium bicarbonate aqueoussolution was added to aqueous layer until pH10 and extracted with ether(100 ml×4).

Combined ethereal layer was washed with brine and then was dried overanhydrous sodium sulfate and evaporated in vacuo. To the residue,benzene (40 ml), benzyl alcohol (21 ml) and p-toluenesulfonicacid.monohydrate (4.76 g) were added and the mixture was heated underreflux for 4 hours. After cooling down to room temperature, the solventwas evaporated in vacuo. To the residue was added water (200 ml) andwashed with ether (100 ml×2). Saturated sodium bicarbonate aqueoussolution was added to aqueous layer until pH10 and extracted with ether(100 ml×4). Combined ethereal layer was washed with brine, dried overanhydrous sodium sulfate and evaporated in vacuo to give benzyl(R)-3-(4-aminophenyl)-2-hydroxypropionate (2.84 g).

NMR (CDCl₃, δ) 2.85 (dd, 1H), 2.6-3.6 (m, 3H), 3.00 (dd, 1H), 4.38 (dd,1H), 5.15 (s, 2H), 6.53 (d, 2H), 6.90 (d, 2H), 7.25-7.4 (m, 5H)

IR (neat):1740 cm⁻¹

Preparation 2

To a solution of benzyl (R)-3-(4-aminophenyl)-2-hydroxypropionate (0.26g) in acetic acid (6 ml) was added paraformaldehyde (0.3 g), and furthersodium cyanoborohydride (0.3 g) was added gradually, and stirred for 3hours at ambient temperature. To sodium bicarbonate solution (25 ml) andice (25 g) was added reaction mixture gradually and was extracted withethyl acetate (50 ml×2). The separated ethyl acetate layer was washedwith brine,dried over anhydrous sodium sulfate and evaporated in vacuo.The resultant crude product was subjected to column chromatography onsilica gel eluting with a mixture of hexane and ethyl acetate (7:3 byvolume). The fractions containing the desired product were combined andevaporated in vacuo to give benzyl(R)-3-(4-dimethylaminophenyl)-2-hydroxypropionate (0.22 g).

NMR (CDCl₃, δ) 2.64 (d, 1H), 2.91 (s, 6H), 2.90 (dd, 1H), 3.04 (dd, 1H),4.43 (ddd, 1H), 5.18 (s, 2H), 6.63 (d, 2H), 7.01 (d, 2H), 7.35 (bs, 5H)

IR (neat):1.733, 1612 cm⁻¹

Preparation 3

To a solution of Boc-MeLeu-OH (1.27 g) and H-D-p-Me₂ NPhLac-OBzl (1.47g) in methylene chloride (20 ml) were added dimethylaminopyridine (0.15g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.hydrochloride(1.01 g) under ice-cooling and stirred for 15 hours. The solvent wasevaporated in vacuo and then water (50 ml) was added to the residue andextracted with ethyl acetate (50 ml×3). The ethyl acetate layer waswashed with brine, dried over anhydrous sodium sulfate and evaporated invacuo. The resultant crude product was subjected to columnchromatography on silica gel eluting with a mixture of hexane and ethylacetate (4:1 by volume). The fractions containing the desired productwere combined and evaporated in vacuo to give Boc-MeLeu-D-p-Me₂NPhLac-OBzl (1.69 g).

NMR (CDCl₃, δ) 0.90 (d, 6H), 1.4-1.65 (m, 12H), 2.63 (s) and 2.68 (s)(3H), 2.93 (s, 6H), 3.05-3.15 (m, 2H), 4.65-4.80 (m) and 4.95-5.20 (m)(4H), 6.62 (d, 2H), 7.03 (d, 2H), 7.1-7.2 (m, 5H)

IR (KBr):1747, 1730, 1693, 1675, cm⁻¹

Preparation 4

To a solution of Boc-MeLeu-D-p-Me₂ NPhLac-OBzl (1.67 g) in a mixedsolvent of methanol (30 ml) and tetrahydrofuran (5 ml) was added 10%palladium-charcoal (0.3 g) and the mixture was subjected tohydrogenation reaction under hydrogen atmosphere (1 atm.) at ambienttemperature for 1.5 hours. The catalyst was filtered off and thefiltrate was evaporated in vacuo to give Boc-MeLeu-D-p-Me₂ NPhLac-OH(1.44 g).

IR (KBr):1741,1694 cm⁻¹

Preparation 5

Boc-MeLeu-D-Lac-OBzl (2.45 g) was used instead of Boc-MeLeu-D-p-Me₂NPhlac-OBzl. Except above matter, Boc-MeLeu-D-Lac-OH (1.77 g) wasobtained according to a similar manner to that of Preparation 4.

IR (KBr):1.742, 1695, 1668 cm⁻¹

Preparation 6

To a mixture of Boc-MeLeu-D-Lac-OH (1.76 g), H-MeLeu-D-Lac-OBzl (2.05g), methylene chloride (40 ml) and triethylamine (1.7 ml) was added bis(2-oxo-3-oxazolidinyl) phosphinic chloride (1.55 g) under ice-coolingand stirred for 28 hours. Water (100 ml) was added to the reactionmixture and extracted with ethyl acetate (50 ml×3). The ethyl acetatelayer was washed with brine, dried over anhydrous sodium sulfate andevaporated in vacuo. The resultant crude product was subjected to columnchromatography on silica gel eluting with a mixture of ethyl acetate andhexane (3:7 by volume). The fractions containing the desired productwere combined and evaporated in vacuo to giveBoc-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (2.29 g).

NMR(CDCl₃, δ):0.85-1.00 (m, 12H), 1.35-1.90 (m, 12H), 1.45 (s,9H),2.80-2.95 (m, 6H), 4.45-5.40 (m, 6H), 7.35 (bs, 5H)

IR(neat):1741, 1693,1667 cm⁻¹

Preparation 7

Boc-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (0.775 g) was used instead ofBoc-MeLeu-D-p-Me₂ NPhLac-OBzl. Except above matter,Boc-MeLeu-D-Lac-MeLeu-D-Lac-OH (0.62 g) was obtained according to asimilar manner to that of Preparation 4.

IR (neat):1740, 1695, 1666 cm⁻¹

Preparation 8

Boc-MeLeu-D-Lac-MeLeu-D-Lac-OH (3.51 g) was used instead ofBoc-MeLeu-D-Lac-OH. Except above matter,Boc-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (4.89 g) was obtainedaccording to a similar manner to that of Preparation 6.

NMR (CDCl₃, δ) 0.80-1.05 (m, 18H), 1.2-1.85 (m, 27H), 2.8-3.1 (m, 9H),4.70-4.8 (m) and 4.9-5.5 (m) (6H), 7.3-7.4 (m, 5H)

IR (KBr):1741, 1695, 1665 cm⁻¹

Preparation 9

Boc-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (4.89 g) was dissolved in4N-hydrogen chloride in ethyl acetate (30 ml) and stirred for 2 hours atambient temperature. After the solvent was evaporated in vacuo, theresidue was azeotroped twice by toluene (20 ml). Hexane (10 ml) andmethylene chloride (10 ml) were added and the solvents were evaporatedin vacuo. This procedure was repeated twice to giveHCl.H-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (4.97 g).

IR (KBr):1742, 1647 cm⁻¹

Preparation 10

To a mixture of Boc-MeLeu-D-p-Me₂ NPhLac-OH (0.82 g), HCl.H-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (1.27 g), N-methylmorpholine(0.85 ml) and methylene chloride (10 ml) was added bis(2-oxo-3-oxazolidinyl) phosphinic chloride (0.72 g) under ice-coolingand stirred for 15 hours. The reaction mixture was evaporated in vacuo,water (50 ml) was added and extracted with ethyl acetate (50 ml×3). Theethyl acetate layer was washed with brine, dried over anhydrous sodiumsulfate and evaporated in vacuo. The resultant crude product wassubjected to column chromatography on silica gel eluting with a mixtureof hexane, ethyl acetate and ethanol (1:3:0.1 by volume). The fractionscontaining the desired product were combined and evaporated in vacuo togive Boc-MeLeu-D-p-Me₂ NPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl(0.69 g).

IR (KBr):1740, 1695, 1663 cm⁻¹ FAB-MS: 1024[M-Boc+H]⁺

Preparation 11

Boc-MeLeu-D-p-Me₂ NPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (0.69g) was used instead of Boc-MeLeu-D-p-Me₂ NPhLac-OBzl. Except abovematter, Boc-MeLeu-D-p-Me₂ NPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH(0.67 g) was obtained according to a similar manner to that ofPreparation 4.

IR (KBr):1739, 1694, 1663 cm⁻¹

Preparation 12

Boc-MeLeu-D-p-Me₂ NPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (0.67 g)was used instead of Boc-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl. Exceptabove matter, 2HCl. H-MeLeu-D-p-Me₂NPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (0.60 g) was obtainedaccording to a similar manner to that of Preparation 9.

IR (KBr):1741, 1640 cm⁻¹

Preparation 13

A suspended solution of benzyl (R)-3-(4-aminophenyl)-2-hydroxypropionate(0.27 g), bis (2-chloroethyl) ether (0.12 ml), potassium carbonate (0.28g) and sodium iodide (0.075 g) in dimethylformamide (1 ml) was heated at70°-90° C. for 7 hours. After cooling down to room temperature, water(50 ml) was added and extracted with ether (25 ml×3). The ether layerwas washed with brine, dried over anhydrous sodium sulfate andevaporated in vacuo. The resultant crude product was subjected to columnchromatography on silica gel eluting with a mixture of hexane, ethylacetate and ethanol (60:35:5 by volume). The fractions containing thedesired product were combined and evaporated in vacuo to give benzyl(R)-2-hydroxy-3-(4-morpholinophenyl) propionate (0.14 g).

NMR (CDCl₃, δ) 2.66 (d, 1H), 2.91 (dd, 1H), 3.05 (dd, 1H), 3.0-3.15 (m,4H), 3.8-3.95 (m, 4H), 4.45 (ddd, 1H), 5.18 (s, 2H), 6.79 (d, 2H), 7.05(d, 2H), 7.3-7.4 (m, 5H)

IR (neat):1734 cm⁻¹ EI-MS 341[M]⁺

Preparation 14

H-D-p-MorPhLac-OBzl (0.90 g) was used instead of H-D-p-Me₂ NPhLac -OBzl.Except above matter, Boc-MeLeu-D-p-MorPhLac-OBzl (1.36 g) was obtainedaccording to a similar manner to that of

Preparation 3.

NMR (CDCl₃, δ) 0.9 (d, 6H) 1.4-1.65 (m, 12H), 2.63 (s) and 2.66 (s)(3H), 3.05-3.2 (m, 6H), 3.85-3.95 (m, 4H), 4.7-4.8 (m) and 4.95-5.25 (m)(4H), 6.80 (d, 2H), 7.07 (d, 2H), 7.1-7.2 (m, 5H)

IR (KBr):1740, 1695 cm⁻¹

Preparation 15

Boc-MeLeu-D-p-MorPhLac-OBzl (1.35 g) was used instead ofBoc-MeLeu-D-p-Me₂ NPhLac-OBzl. Except above matter,Boc-MeLeu-D-p-MorPhLac-OH (1.08 g) was obtained according to a similarmanner to that of Preparation 4.

IR (KBr):1742, 1695 cm⁻¹

Preparation 16

Boc-MeLeu-D-p-MorPhLac-OH (1.54 g) was used instead of Boc-MeLeu-D-p-Me₂NPhLac-OH. Except above matter,Boc-MeLeu-D-p-MorPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (1.60 g)was obtained according to a similar manner to that of Preparation 10.

NMR (CDCl₃, δ) 0.8-1.0 (m, 24H), 1.2-1.9 (m, 30H), 2.7-3.15 (m, 18H),3.8-3.9 (m, 4H), 4.65-4.75 (m) and 4.9-5.5 (m) (10H), 6.82 (d, 2H), 7.13(d, 2H), 7.3-7.4 (m, 5H)

IR (KBr):1740, 1695, 1667 cm⁻¹ FAB-MS: 1166[M+H]⁺

Preparation 17

Boc-MeLeu-D-p-MorPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (1.59 g)was used instead of Boc-MeLeu-D-p-Me₂ NPhLac-OBzl. Except above matter,Boc-MeLeu-D-p-MorPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (1.56 g)was obtained according to a similar manner to that of Preparation 4.

IR (KBr):1739, 1695, 1680 cm⁻¹

Preparation 18

Boc-MeLeu-D-p-MorPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (1.56 g)was used instead of Boc-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl. Exceptabove matter,2HCl.H-MeLeu-D-p-MorPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH 1.66 g)was obtained according to a similar manner to that of Preparation 9.

IR (KBr):1743, 1647 cm⁻¹

Preparation 19

Boc-Tyr(Me)-OH (5.1 g) was dissolved in 4N-hydrogen chloride in dioxane(87.5 ml) and stirred for 2 hours under ice-cooling. After dioxane wasevaporated in vacuo, the residue was dissolved in 6N-hydrochloric acidaqueous solution (45 ml) and sodium nitrite (1.9 g) was added byportions at 0° C. After stirring for 4 hours, the reaction solution wasextracted with ether (100 ml×3). The ether layer was washed with brine,dried over calcium chloride and evaporated in vacuo. To the residue,benzene (30 ml), benzyl alcohol (3.4 ml) and p-toluenesulfonicacid.monohydrate (0.22 g) were added and the mixture was heated underreflux for 3 hours by using Dean Stark apparatus. After cooling down toroom temperature, the solvent was evaporated in vacuo. The resultantcrude product was subjected to column chromatography on silica geleluting with a mixture of hexane and ethyl acetate (10:1 by volume). Thefractions containing the desired product were combined and evaporated invacuo to give benzyl (S)-2-chloro-3-(4-methoxyphenyl) propionate (1.79g). NMR (CDCl₃, δ):3.12 (d d, 1 H), 3.29 (d d, 1H), 3.78 (s, 3H), 4.44(t, 1H), 5.07-5.25 (m, 2H), 6.77-7.36 (m, 9H)

Preparation 20

To a solution of Boc-MeLeu-OH (1.37 g) in a mixed solvent of methanol(30 ml) and water (10 ml) was added 20% cesium carbonate aqueoussolution to pH 7.0. After the solvent was evaporated in vacuo, theresidue was azeotroped three times by toluene (10 ml). The residue wasdissolved in dimethylformamide (20 ml) and then benzyl(S)-2-chloro-3-(4-methoxyphenyl) propionate (1.7 g) was added underice-cooling and stirred for 24 hours at ambient temperature. Thereaction mixture was poured into water (150 ml) and extracted with ether(100 ml×3). The ether layer was washed with brine, dried over anhydrousmagnesium sulfate and evaporated in vacuo. The resultant crude productwas subjected to column chromatography on silica gel eluting with amixture of ethyl acetate and hexane (1:8 by volume). The fractionscontaining the desired product were combined and evaporated in vacuo togive Boc-MeLeu-D-p-MeOPhLac-OBzl (1.59 g).

NMR (CDCl₃, δ):0.90 (d, 6H), 1.41 (s) and 1.49 (s) (9H), 1.40-1.58 (m,3H), 2.62-2.67 (m, 3H), 3.06-3.15 (m, 2H), 3.77 (s, 3H), 4.68-4.80 (m)and, 4.97-5.29 (m) (4H), 6.78 (d, 2H), 7.06 (d, 2H), 7.26-7.36 (m, 5H).

Preparation 21

To a solution of Boc-MeLeu-D-p-MeOPhLac-OBzl (1.36 g) in methanol (15ml) was added 10% palladium-charcoal (0.4 g) and the mixture wassubjected to hydrogenation reaction under hydrogen atmosphere (1 atm.)at ambient temperature for 45 minutes. The catalyst was filtered off andthe filtrate was evaporated in vacuo to give Boc-MeLeu-D-p-MeOPhLac-OH(1.08 g).

NMR (CDCl₃, δ):0.89-0.95 (m, 6H), 1.44 (s, 9H), 1.44-1.79 (m, 3H),2.66-2.82 (m, 3H), 3.01-3.20 (m, 2H), 3.79 (s, 3H), 4.40-4.75 (m, 1H),5.15-5.38 (m, 1H), 6.82 (d, 2H), 7.14 (d, 2H)

Preparation 22

Boc-MeLeu-D-p-MeOPhLac-OH (0.89 g) was used instead of Boc-MeLeu-D-p-Me₂NPhLac-OH. Except above matter,Boc-MeLeu-D-p-MeOPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (1.06 g)was obtained according to a similar manner to that of Preparation 10.

NMR (CDCl₃, δ) 0.85-1.0 (m, 24H), 1.4-1.9 (m, 21H), 2.75-3.15 (m, 14H),3.78 (s, 3H), 4.65-4.75 (m) and 4.9-5.5 (m) (10H), 6.82 (d, 2H), 7.15(d, 2H), 7.3-7.4 (m, 5H)

IR (KBr):1740, 1695, 1664 cm⁻¹ FAB-MS: 1011[M-Boc+H]⁺

Preparation 23

Boc-MeLeu-D-p-MeOPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (1.05 g)was used instead of Boc-MeLeu-D-p-Me₂ NPhLac-OBzl. Except above matter,Boc-MeLeu-D-p-MeOPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (1.06 g)was obtained according to a similar manner to that of Preparation 4.

IR (KBr):1740, 1695, 1664 cm⁻¹

Preparation 24

Boc-MeLeu-D-p-MeOPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (0.95 g)was used instead of Boc-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl. Exceptabove matter,HCl.H-MeLeu-D-p-MeOPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (1.01 g)was obtained according to a similar manner to that of Preparation 9.

IR (KBr):1742, 1664 cm⁻¹

Preparation 25

To a solution of benzyl (R)-3-(4-aminophenyl)-2-hydroxypropionate (1.36g) and potassium carbonate (1.04 g) in a mixed solvent of 1,4-dioxane(15 ml) and water (3 ml) was added methyl chlorocarbonate (0.46 ml)dropwise under ice-cooling and stirred for 4 hours. To the reactionmixture water (100 ml) was added and extracted with ethyl acetate (50ml+25 ml). The ethyl acetate layer was washed with 5% citric acidaqueous solution and brine successively, dried over anhydrous sodiumsulfate and evaporated in vacuo. The resultant crude product wassubjected to column chromatography on silica gel eluting with a mixtureof hexane and ethyl acetate (7:3˜6:4 by volume). The fractionscontaining the desired product were combined and evaporated in vacuo togive benzyl (R)-2-hydroxy-3-(4-methoxycarbonylaminophenyl) propionate(1.65 g).

NMR (CDCl₃, δ):1.60 (b s, 1H), 2.93 (dd, 1H), 3.8 (dd, 1H), 3.77 (s,3H), 4.46 (dd, 1H), 5.18 (s, 2H), 6.58 (bs, 1H), 7.07 (d, 2H), 7.24 (d,2H), 7.3-7.4 (m, 5H)

IR (KBr):1714 cm⁻¹

Preparation 26

H-D-p-CbmNHPhLac-OBzl (1.35 g) was used instead of H-D-p-Me₂NPhLac-OBzl. Except above matter,Boc-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-OBzl (2.82 g) was obtainedaccording to a similar manner to that of Preparation 3.

NMR (CDCl₃, δ):0.90 (d, 6H), 1.4-1.65 (m, 12H), 2.63 (s) and 2.65 (s)(3H), 3.05-3.15 (m, 2H), 3.77 (s, 3H), 4.65-4.75 (m) and 4.95-5.25 (m)(4H), 6.55 (bs, 1H), 7.08 (d, 2H), 7.2-7.4 (m, 7H)

IR (KBr):1735, 1695, 1685 cm⁻¹

Preparation 27

To a solution of Boc-MeLeu-D-p-CbmNHPhLac-OBzl (2.80 g) in methanol (25ml) was added 10% palladium-charcoal (0.5 g) and ammoniumformate (0.63g) under nitrogen atmosphere and the mixture was stirred at ambienttemperature for 2 hours. The catalyst was filtered off and the filtratewas evaporated in vacuo. To the obtained residue was added water (100ml) and 5% citric acid aqueous solution (50 ml) and extracted with ethylacetate: (50 ml×2). The ethyl acetate layer was washed with 5% citricacid aqueous solution and brine successively, dried over anhydroussodium sulfate and evaporated in vacuo to giveBoc-MeLeu-D-p-CbmNHPhLac-Oh (2.13 g).

IR (KBr):1734, 1695, 1675 cm⁻¹

Preparation 28

Boc-MeLeu-D-p-CbmNHPhLac-OH (2.11 g) was used instead ofBoc-MeLeu-D-Lac-OH. Except above matter,Boc-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-OBzl (3.29 g) was obtainedaccording to a similar manner to that of Preparation 6.

NMR (CDCl₃, δ):0.85-0.95 (m, 12H), 1.4-1.7 (m, 18H), 2.77 (s), 2.83 (s)and 2.89 (s) (6H), 3.0-3.1 (m, 2H), 3.77 (s, 3H), 4.65-4.80 (m) and4.9-5.5 (m) (6H), 6.59 (bs, 1H), 7.16 (d, 2H), 7.3-7.4 (m, 7H)

IR (KBr):1735 cm⁻¹

Preparation 29

Boc-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-OBzl (3.28 g) was used instead ofBoc-MeLeu-D-p-CbmNHPhLac-OBzl. Except above matter,Boc-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-OH (2.81 g) was obtained accordingto a similar manner to that of Preparation 27.

IR (KBr):1735, 1696, 1671 cm⁻¹

Preparation 30

To a solution of Boc-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (1.5 g) in methylenechloride (10 ml) was added trifluoroacetic acid (5 ml) and the mixturewas stirred under ice-cooling for 1 hour. After the solvent wasevaporated in vacuo, water (50 ml) and sodium bicarbonate was addedsuccessively to the residue until pH9. The mixture was extracted withether (50 ml×3) and the ether layer was washed with brine, dried overanhydrous sodium sulfate and evaporated in vacuo to giveH-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (1.25 g).

IR (KBr):1738, 1665 cm⁻¹

Preparation 31

Boc-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-OH (2.81 g) was used instead ofBoc-MeLeu-D-p-Me₂ NPhLac-OH and H-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (2.27 g)was used instead of H-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl. Exceptabove matter,Boc-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (4.75g) was obtained according to a similar manner to that of Preparation 10.

NMR (CDCl₃, δ):0.8-1.05 (m, 24H), 1.15-1.8 (m, 30H), 2.75-3.15 (m, 14H),3.77 (s, 3H), 4.4-4.5 (m), 4.65-4.75 (m) and 4.9-5.5 (m) (10 H), 6.60(bs, 1H), 7.15-7.4 (m, 9H)

IR (KBr):1735, 1694, 1666 cm⁻¹

Preparation 32

Boc-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OBzl (4.7g) was used instead of Boc-MeLeu-D-p-CbmNHPhLac-OBzl. Except abovematter, Boc-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH(4.37 g) was obtained according to a similar manner to that ofPreparation 27.

IR (KBr): 1734, 1694, 1663 cm⁻¹

Preparation 33

Boc-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (4.37 g)was used instead of Boc-MeLeu-D-p-NPhLac-OBzl. Except above matter,HCl.H-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (4.08g) was obtained according to a similar manner to that of Preparation 9.

IR (KBr):1742, 1647 cm⁻¹

EXAMPLE 1

To a solution of 2HCl.H-MeLeu-D-p-Me₂NPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (0.60 g) in methylenechloride (122 ml) was added N-methyImorpholine (0.35 ml) and his(2-oxo-3-oxazolidinyl) phosphinic chloride (0.23 g) under ice-coolingand stirred for 15 hours.

The reaction mixture was evaporated in vacuo, and water (50 ml) wasadded and extracted with ethyl acetate (50 ml×3). The ethyl acetatelayer was washed with brine, dried over anhydrous sodium sulfate andevaporated in vacuo. The resultant crude product was subjected to columnchromatography on silica gel Muting with a mixture of hexane, ethylacetate and ethanol (1:1:0.1 V/V). The fractions containing the desiredproduct were combined and evaporated in vacuo give ##STR4## (0.33 g).

NMR (CDCl₃, δ) 0.75-1.1 (m, 24H), 1.2-1.9 (m, 21H), 2.75-3.2 (m, 20H),4.4-5.8 (m, 8H), 6.64 (d, 2H), 7.10 (d, 2H)

IR (KBr):1741, 1663 cm⁻¹ FAB-MS: 916[M+H]⁺

EXAMPLE 2

The compound, ##STR5## (0.86 g) was obtained according to a similarmanner to that of Example 1 by using2HCl.H-MeLeu-D-p-MorPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (1.66g) instead of 2HCl.H-MeLeu-D-p-Me₂NPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH.

NMR (CDCl₃, δ) 0.75-1.1 (m, 2 4 H), 1.2-1.9 (m, 21H), 2.8-3.2 (m, 18H),3.8-3.9 (m, 4H), 4.45-4.55 (m) and 5.0-5.7 (m) (8H), 6.82 (d, 2H), 7.13(d, 2H)

IR (KBr):1741, 1663 cm⁻¹ FAB-MS 958[M+H]⁺

EXAMPLE 3

The compound, ##STR6## (0.422 g) was obtained according to a similarmanner to that of Example 1 by usingHCl.H-MeLeu-D-p-MeOPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (0.80 g)instead of 2HCl.H-MeLeu-D-p-Me₂NPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH.

NMR (CDCl₃, δ) 0.75-1.1 (m, 24H), 1.2-2.0 (m, 21H), 2.8-3.2 (m, 14H),3.78 (s, 3H), 4.45-4.55 (m) and 5.0-5.7 (m) (8H), 6.75-6.85 (m, 2H),7.1-7.2 (m, 2H)

IR (KBr):1743, 1663 cm⁻¹ FAB-MS: 903[M+H]⁺

EXAMPLE 4

To a solution of ##STR7## (59.5 mg) in methylene chloride was addedfuming nitric acid (0.12 ml) under ice-cooling and stirred for 30minutes at the same temperature.

The reaction solution was added gradually to saturated sodiumbicarbonate aqueous solution (40 ml) and extracted with ethyl acetate(40 ml×3). The ethyl acetate layer was washed with brine, dried overanhydrous sodium sulfate and evaporated in vacuo to give crude product(62.9 g) of ##STR8##

NMR (CDCl₃, δ) 0.75-1.1 (m, 24H), 1.2-2.0 (m, 21H), 2.75-3.3 (m, 14H),4.45-4.55 (m) and 5.0-5.8 (m) (8H), 7.2-7.3 (m, 2H), 8.1-8.2 (m, 2H)

IR (KBr):1742, 1663 cm⁻¹ FAB-MS: 940[M+Na]⁺

EXAMPLE 5

To a solution of crude product (53 mg) of ##STR9## in methanol (8 ml)was added 10% palladium-charcoal (0.03 g) and the mixture was subjectedto hydrogenation reaction under hydrogen atmosphere (1 atm.) at ambienttemperature for 4 hours. The catalyst was filtered off and the filtratewas evaporated in vacuo. The resultant crude product was subjected tocolumn chromatography on silica gel eluting with a mixture of hexane,ethyl acetate and ethanol (60:35:5 V/V). The fractions containing thedesired product were combined and evaporated in vacuo to give ##STR10##(25 mg).

NMR (CDCl₃, δ) 0.8-1.1 (m, 24H), 1.15-1.95 (m, 21H), 2.7-3.15 (m, 14H),4.45-4.55 (m) and 5.0-5.7 (m) (8H), 6.55-6.65 (m, 2H), 6.95-7.1 (m, 2H)

IN (KBr):1740, 1658 cm⁻¹ FAB-MS: 888[M+H]⁺

EXAMPLE 6

A suspended solution of ##STR11## (20 mg), bis (2-chloroethyl) ether(0.004 ml), potassium carbonate (9.4 mg) and sodium iodide (3.4 mg) indimethylformamide (0.2 ml) was heated at 75° C. for 15.5 hours. Aftercooling down to room temperature, water (20 ml) was added and extractedwith ethyl acetate (20 ml×3). The ethyl acetate layer was washed withbrine, dried over anhydrous sodium sulfate and evaporated in vacuo. Theresultant crude product was subjected to column chromatography on silicagel eluting with a mixture of hexane, ethyl acetate and ethanol (60:35:5V/V). The fractions containing the desired product were combined andevaporated in vacuo to give ##STR12## (11.9 mg).

NMR (CDCl₃, δ) 0.75-1.1 (m, 9.4 H), 1.2-1.9 (m, 21H), 2.8-3.2 (m, 18H),3.8-3.9 (m, 4H), 4.45-4.55 (m) and 5.0-5.7 (m) (8H), 6.82 (d, 2H), 7.13(d, 2H)

IR (KBr):1741, 1663 cm⁻¹ FAB-MS: 958[M+H]⁺

EXAMPLE 7

The compound, ##STR13## (1.76 g) was obtained according to a similarmanner to that of Example 1 by usingHCl.H-MeLeu-D-p-CbmNHPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH (4.08g) was used instead of 2HCl.H-MeLeu-D-p-Me₂NPhLac-MeLeu-D-Lac-MeLeu-D-Lac-MeLeu-D-Lac-OH.

NMR (CDCl₃, δ):0.8-1.1 (m, 24H), 1.3-1.8 (m, 21H), 2.6-3.2 (m, 14H),3.77 (s, 3H), 4.4-4.55 (m) and 5.0-5.75 (m) (8H), 6.55-6.8 (m, 1H),7.15-7.20 (m, 2H), 7.25-7.4 (m, 2H)

IR (KBr):1741, 1663 cm⁻¹ FAB-MS: 968[M+Na]⁺

EXAMPLE 8 ##STR14## (0.946 g) was added to 30% hydrogen bromide inacetic acid and the mixture was stirred at ambient temperature for 8hours. After the solvent was evaporated in vacuo, water (50 ml) andethyl acetate (25 ml) was added to the residue, neutralized with sodiumbicarbonate. The ethyl acetate layer was separated and the aqueous layerwas extracted with ethyl acetate (25 ml×2). The combined ethyl acetatelayer was washed with 5% sodium bicarbonate aqueous solution (50 ml) andbrine (50 ml×2) successively, dried over anhydrous sodium sulfate andevaporated in vacuo to give ##STR15## (0.92 g).

IR (KBr):1740, 1658 cm⁻¹

EXAMPLE 9 ##STR16## (0.92 g) was used instead of benzyl(R)-3-(4-aminophenyl)-2-hydroxypropionate. Except above matter,##STR17## (0.71 g) was obtained according to a similar manner to that ofPreparation 2.

NMR (CDCl₃, δ):0.75-1.1 (m, 24H), 1.2-1.9 (m, 21H), 2.75-3.2 (m,20H)4.4-5.8 (m, 8H), 6.64 (d, 2H), 7.10 (d, 2H)

IR (KBr):1741, 1663 cm⁻¹ FAB-MS: 916[EM+H]⁺

EFFECT

The compounds of the present invention have strong activities againstparasites in the alimentary canal and medicines which are also effectiveagainst parasites in the tissues were found.

What we claim is:
 1. A compound of the general formula: ##STR18##wherein A is a substituted benzyl group, A^(a), B and D are each loweralkyl, andC is hydrogen or lower alkyl,or a salt thereof.
 2. A compoundof claim 1, whereinA is a benzyl group substituted by cyclic amino,di-lower alkylamino or lower alkoxy, B and D are each isopropyl, andA^(a) and C are each methyl,or a salt thereof.
 3. A compound of claim 1,whereinA is a benzyl group substituted by morpholino, dimethylamino ormethoxy,or a salt thereof.
 4. A compound of claim 1, whereinA is abenzyl group substituted by nitro, amino or protected amino, B and D areeach isopropyl, and A^(a) and C are each methyl,or a salt thereof.
 5. Acompound of the formula: ##STR19## or a salt thereof.
 6. A compound ofthe formula: ##STR20##
 7. A compound of the formula: ##STR21##
 8. Aprocess for the preparation of a compound of the formula: ##STR22## or asalt thereof, which comprises subjecting a compound of the formula:##STR23## or a salt thereof to cyclic-alkylation, wherein B and D areeach lower alkyl,A^(a) and C are each hydrogen or lower alkyl, A3 is abenzyl group which has amino, or benzyl group which substituted by aminoand lower alkoxy, A5 is a benzyl group substituted by cyclic amino, or abenzyl group substituted by cyclic amino and lower alkoxy.
 9. Aparasiticide which comprises, as an active ingredient, a compound ofclaim 1 or a salt thereof.
 10. A compound of claim 1, whereinA is abenzyl group substituted with a morpholino group, B and D are eachisobutyl, and A^(a) and C are each methyl,or a salt thereof.
 11. Acompound of claim 1, whereinA is a benzyl group substituted with acyclic amino group, B and D are each isobutyl, and A^(a) and C are eachmethyl,or a salt thereof.